Review of extranodal extension grading for esophageal cancer: three-dimensional radiologic, surgical and pathologic findings

Introduction

Background

The American Joint Committee on Cancer (AJCC) cancer staging manual 8^th edition of head and neck cancer defines extranodal extension (ENE) as the extension distance of cancer from the lymph node (LN) capsule (1,2). ENE is one of the most important survival predictors in head and neck squamous cell carcinoma (3). The revised 2017 tumor, lymph node, metastasis (TNM) classification defined ENE for head and neck cancers and included ENE in the determination of the pathological N factor, as clinical evidence has established that ENE is a prognostic indicator for head and neck cancers (2-4). Therefore, ENE is now incorporated in the TNM classification of these malignancies. In contrast, ENE definition and prognostic value in esophageal and gastrointestinal malignancies remain unclear. Given the biological and clinical similarities between head and neck cancers and esophageal cancer, exploring the role of ENE in esophageal cancer may provide valuable insights for improving treatment strategies and patient outcomes. ENE grading of esophageal squamous cell carcinoma (ESCC) patients may be important for estimating prognosis (5). ENE in adenocarcinoma as well as squamous cell carcinoma has a negative impact on prognosis in esophageal cancer (4,6,7).

Despite the significance of LN metastases as a major prognostic factor in esophageal cancer, inconsistencies can be observed in radiographic findings and pathological findings between preoperative clinical LN diagnosis and final pathological evaluation. It is difficult for physicians to accurately and precisely diagnose clinical LN metastasis by the currently available modalities, including computed tomography (CT), fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography/CT, and endoscopic ultrasound (EUS) with or without fine-needle aspiration (8,9). Furthermore, underdiagnosis of micrometastasis or small LN metastasis is common in the analysis of resected specimens (10). However, the size of LN metastasis with ENE is large (11), and LN metastasis with ENE can be detected in preoperative CT scans in patients with nodal-positive head and neck squamous cell carcinoma (12-14). In esophageal cancer patients, LN metastasis with ENE might also be detected because of the LN size and histological type, as in head and neck cancer (10).

Accurate clinical diagnosis of ENE is important to plan the appropriate multimodality treatment and to predict not only prognosis but also the difficulty of the operative procedure during LN dissection. In this article, we provide a detailed review of the correlation between the three-dimensional CT (3D-CT) imaging findings and pathological findings with the results of the surgical findings. We discuss a representative ENE case series and examine key imaging findings suggesting the presence of ENE in the cervical, thoracic and abdominal fields.

Rationale and knowledge gap

Esophageal cancer shows a high risk cancer for metastasis of LNs in in the cervical, thoracic and abdominal regions (15). In Japan, radical dissection of cervical, thoracic and abdominal LNs, known as three-field lymphadenectomy, is routinely conducted for esophageal cancer patients to decrease the risk of LN recurrence (16). However, a substantial percentage of esophageal cancer patients still show local recurrence and shortened survival time after surgical treatment (17).

The 2017 TNM classification of head and neck cancer defined ENE as the extension distance of cancer from the LN capsule (2). ENE is further subdivided to clinical ENE (cENE) and pathological ENE (pENE). The AJCC Cancer Staging Manual defines pENE as the “extension of metastatic tumor (tumor present within the confines of the LN and extending through the LN capsule into the surrounding connective tissue, with or without associated stromal reaction” (1).

In esophageal cancer, contrast-enhanced CT is appropriate for diagnosis of cENE. Magnetic resonance image (MRI) of mediastinal tumors is hampered by the respiratory motion and pulsation artifacts of the aorta or the beating heart. Therefore, precise analysis of mediastinal LNs by MRI is difficult. In ENE imaging, various modalities such as CT, MRI, and ultrasound are used, with each offering specific benefits. 3D-CT, however, provides a more detailed analysis of the target LN by offering high-resolution images across three planes: longitudinal, short axis, and axial maximum diameter. This technique allows for a three-dimensional construction, enhancing the ability to detect irregular borders and infiltration of adjacent planes—key indicators of ENE. Compared to MRI and ultrasound, 3D-CT’s superior spatial resolution and comprehensive visualization of the surrounding anatomical structures make it particularly effective in assessing ENE.

Objective

We previously reported the relationship between ENE grading (based on the extent of tumor spreading beyond the LN capsule) and the prognosis of ESCC patients (5). The definitions of pENE grading and intranodal involvement (INI) are listed below (Figure 1):

• Grade 1: tumor extending ≤1 mm beyond the nodal capsule;
• Grade 2: tumor extending >1 mm beyond the nodal capsule;
• Grade 3: a metastatic LN in which carcinoma extended beyond the original nodal area accompanied by complete destruction of nodal architecture.
• INI: tumor remaining within the original LN without any sign of ENE.

Figure 1 ENE histologic features. (A) INI: tumor remain within the original lymph node without any sign of ENE (hematoxylin-eosin stain; original magnification, ×20). (B) Grade 1 shows tumor extending ≤1 mm beyond the nodal capsule (indicated by the yellow line on the schematic) (hematoxylin-eosin stain; original magnification, ×5). (C) Grade 2 shows tumor extending >1 mm beyond the nodal capsule (yellow line on the schematic) (hematoxylin-eosin stain; original magnification, ×5). (D) Grade 3 shows metastatic lymph nodes in which carcinoma extend beyond the original nodal area (dotted circle), accompanied by complete destruction of nodal architecture (hematoxylin-eosin stain; original magnification, ×5). Adapted from Okada et al. (5), Impact of pathologically assessing extranodal extension in the thoracic field on the prognosis of esophageal squamous cell carcinoma. Surgery 2019;165(6):1203-1210. ENE, extranodal extension; INI, intranodal involvement.

Patients

Twenty-three esophageal cancer patients who had metastatic LNs dissected during surgery and 3D-CT analysis were enrolled in this study (Table 1).

Diagnosis for cENE

In head and neck cancer, some studies reported significant correlations between pathological ENE and several contrast-enhanced CT findings, such as largest diameter >10 mm (18), infiltration of adjacent planes (19,20), irregular border (12,20) and heterogeneity (18-20). In contrast, there is no established definition of clinical ENE in esophageal cancer, and clinical ENE is not routinely evaluated in clinical radiographic assessments of esophageal cancer.

We analyzed clinical ENE in esophageal cancer. The diagnostic performance of CT demonstrated a specificity of 35.3% and a sensitivity of 53.8% for diagnosing pENE. The conventional CT diagnostic method showed moderate agreement, with a Kappa coefficient of 0.41 (Table 2).

We used a multidetector CT scanner (Aquilon One, Canon Medical Systems, Otawara, Japan) to perform 3D-CT. Patients were first evaluated with an enhanced CT scan. CT scans were performed as briefly described as follows: tube voltages =120 kVp; gantry rotation time =0.5 s; pitch factor =0.813, collimation =0.5-mm × 80 row; and automatic current modulation. Before scanning began, contrast material containing 300 mg of iohexol/mL (Omnipaque, GE Healthcare, Chicago, IL, USA) was injected through a vein by means of a power injector at a 600 mgI/kg for 30 sec through at the antecubital vein. Axial slices were reconstructed with a 1.0-mm slice thickness at 0.3-mm intervals. The obtained images were transferred and processed with a standalone Zio Station2 (Ziosoft Co. Ltd., Tokyo, Japan). Three-dimensional CT LN images were produced by a threshold technique. Then, radiological views of the 3D CT image were constructed with the direction of the surgical approach and pathological slide. The window level of the 3D image was set at 40 Hounsfield units, and the window width was set at 100 Hounsfield units; these are the same values as those of conventional 2D CT images. A LN border showing an irregular shape and adjacent thick high-density areas on 3D-CT image indicates the presence of ENE.

Gap between clinical imaging and pathological view

The presence of an irregular border of the LN, which indicates a disrupted capsule, is one of the most important histological observations in the diagnosis of ENE. In addition, inconsistencies between radiographic findings and pathological findings can be observed; CT imaging findings did not completely agree with pathological ENE findings because of limitations by the constructed axial view. The pathological view of LNs is initiated by cutting at the maximum diameter. The pathological findings did not always match CT findings because of different views during analysis (Figure 2).

Figure 2 Gap between radiographic findings and pathological findings regarding viewpoint. (A) In the specimen, the lymph node is cut at the maximum diameter axis. This schema shows lymph node structures, including afferent lymphatic vessels, nodule, capsule, sinus, efferent lymphatic vessel, and hilum. The cutting plane does not always include the hilum. (B) This schema shows imaging planes by the constructed view of CT. The lymph node is a three-dimensional sphere structure. CT imaging planes were not always equal to the cutting plane in pathology. Although blue arrow shows lymph node examined axial plain, we cannot know the correct examined plane or not. CT, computed tomography.

Cervical field

The dissected cervical field LNs mainly include the cervical paraesophageal LNs (No. 101) and supraclavicular LNs (No. 104). The No. 101 LNs are located around the cervical esophagus, including LNs located along the recurrent laryngeal nerve and the cervical paratracheal LNs. The lateral boundary is the medial border of the carotid sheath. The No. 104 LNs are located in the supraclavicular fossa, extending from the lower border of the cricoid cartilage superiorly to the clavicle inferiorly including the lower internal deep cervical LNs. The medial boundary is the medial border of the carotid sheath. A distinction between left and right must be included for both No. 101 and No. 104 LNs (21). Metastasis at No. 101 is from the lymphatic chain along the paraesophageal and recurrent nerve. Metastasis at No. 104 is from the supraclavicular and internal jugular vein lymphatic chain (22).

Cases with cervical LN invasion are shown in Figures 3-6. A 74-year-old man with recurrent metastatic right cervical paratracheal (No. 101R) LN. No. 101R LN metastasis with ENE was suspected of invasion to the trachea and common carotid artery. Whether the ENE has invaded the common carotid artery and trachea determines the surgical procedure with artery and trachea wall en bloc resection and reconstruction (Figure 3). The pathological finding did not show invasion of these other organs, despite the highly suspected invasion in preoperative analyses (Figure 4).

Figure 3 A 74-year-old man with recurrent metastatic right cervical paratracheal (No. 101R) lymph node. (A) Contrast-enhanced computed tomography scans. (A-1) Axial view, (A-2) coronal view, (A-3) sagittal view. The irregular border of No. 101R ENE was suspected of invasion CA adjacent plane (red arrow) and TR (blue arrow). (B-1,B-2) CA and lateral tracheal wall were en bloc resected with LN because of suspected invasion. (C-1,C-2) A macroscopic specimen shows no invasion of the CA (red arrow) and TR (blue arrow). The black slash in C-1 shows pathological examined plane (C-2). BA, brachiocephalic artery; CA, carotid artery; ENE LN, metastatic lymph node with extranodal extension; TR, trachea.

Figure 4 The pathological slide of No. 101R lymph node from Figure 3 case. (A) Micrograph of a dissected lymph node stained with hematoxylin and eosin. No invasion of TR is observed (hematoxylin-eosin stain; original magnification). (B) Micrograph of a dissected lymph node stained with hematoxylin and eosin. No invasion of CA is observed (hematoxylin-eosin stain; original magnification, ×20). Red arrow shows CA, blue arrow shows TR. CA, carotid artery; TR, trachea.

Figure 5 A 78-year-old man with metastatic No. 101L lymph node. (A) Contrast-enhanced computed tomography scans. (A-1) Axial view, (A-2) 3D contrast view with enhanced TR. ENE was suspected of invasion the TR (blue arrow). (B) Lt-RN was en bloc resected with LN due to suspected of invasion. No. 101L ENE was suspected of invasion the Lt-RN (blue arrow). (C) A macroscopic specimen shows ENE Grade 3 (hematoxylin-eosin stain; original magnification). CA, carotid artery; Eso, esophagus; ENE, extranodal extension; LN, lymph node; SCA, subclavian artery; SCV, subclavian vein; Lt-RN, left recurrent nerve; TR, trachea.

Figure 6 A 77-year-old woman with metastatic No. 104R lymph node. The No. 104R with ENE (yellow arrow) was suspected of invasion to the IJV (A-1) and SCV (A-2). In contrast to the left side, the right IJV and SCV were occupied by ENE LN. Right IJV and SCV were en bloc resected with LN because of ENE invasion. In the surgical specimen, the red dashed line indicates the examined plane where the ENE LN was suspected of invading the IJV (B-1), while the blue dashed line indicates the examined plane suspected of invading the SCV (B-2). *, TR; †, Eso; ‡, CA; §, SCA. CA, carotid artery; ENE, extranodal extension; Eso; esophagus; IJV, internal jugular vein; SCA, subclavian artery; SCV, subclavian vein; TR, trachea.

Metastasis at No. 101L LN with ENE may invade the left recurrent nerve and trachea wall (Figure 5). A 78-year-old man with metastatic No. 101L LN. The 3D-contrast CT with enhanced trachea shows the invasion of the trachea lateral wall by ENE LN. The trachea lateral wall was not resected but the left recurrent nerve was en bloc resected with LN because of ENE invasion. In this case, the en bloc-resected left recurrent nerve was required for reconstruction. If en bloc resection of the partial lateral trachea wall is needed, reconstruction by musculocutaneous flap reconstruction is required. Therefore, radiologists and surgeons should assess the degree of ENE invasion of the recurrent nerve, trachea and common carotid artery at No. 101 LN with ENE.

No. 104 LN metastases may invade the internal jugular vein and subclavian vein. If LN metastases adhering to these veins are observed, the periosteum should be considered for en bloc resection (Figure 6). A 77-year-old woman with metastatic No. 104R LN. This case showed only axial views because of emergency case, and we could not perform the routine CT scan protocol and capture the surgical field. The CT views showed that LN had the capsule; however, the right IJV and SCV were completely absent compared with the opposite side. These findings suggest invasion of the metastatic LN with ENE to the vanished structures. There was no pathological evidence of ENE invasion (Figure 7).

Figure 7 The pathological slides of No. 104 R lymph node from Figure 6 case. Images of a dissected lymph node (a,c) and hematoxylin and eosin staining (b,d). (A) a. Surgical specimen. b. Micrograph of LN from (a) (hematoxylin-eosin stain). The blue dashed line square shows magnified view. c. Magnification of (b). *, indicates the area between ENE LN and IJV (hematoxylin-eosin stain; original magnification, ×5). (B) d. Surgical specimen. e. Three micrographs of LN from (d) (hematoxylin-eosin stain). The blue dashed line square shows magnified view; f. Magnification of (e). The metastatic LN in which carcinoma extended beyond the original nodal area accompanied by complete destruction of nodal architecture. ENE grade 2. *, indicates the area of ENE (hematoxylin-eosin stain; original magnification, ×5). ENE LN, metastatic lymph node with extranodal extension; IJV, internal jugular vein.

Few cases show No. 104 LN metastasis from esophageal cancer that invades other adjacent tissues and structures, including the sternocleidomastoid muscle, phrenic nerve, transverse artery and anterior oblique muscle. These invasion patterns are associated with the lymphatic chain route.

Bulky swollen No. 101L LNs were highly suspected of ENE (Figure 8). A 75-year-old woman with metastatic No. 101L LN with INI metastasis. Analyses of surgically resected specimens revealed a metastatic cervical LN suspected with ENE. However, the pathological findings showed metastatic tumor remaining within the original LN capsule, which was the INI metastatic LN. Macroscopic lesion of well differentiated and hyperkeratosis of tumor might match the non-contrasted area in the 3D-CT view of the metastatic LN. This case was misdiagnosed as positive for ENE from the findings of the irregular enhanced LN border. This case might suggest the limitation for the alone 3D-CT analysis of the metastatic LN capsule.

Figure 8 A 75-year-old woman with metastatic No.101L LN with INI metastasis. (A) Contrast-enhanced computed tomography scans. (A-1) Axial view with the enhanced trachea, (A-2) 3D contrast view. Both views showed the irregular border of No.101L LN suspected of ENE invasion to the left RN (yellow arrow). (B) Surgical view. The top is the cranial side, and the bottom is the caudal side. No.101L (yellow arrows) was suspected of ENE invasion to the Lt-RN (blue arrow). (C) Surgical specimen and macroscopic and microscopic views. (C-1) Green ink shows the dissection area from the left RN (green arrow). (C-2) The macroscopic view shows the same area (green arrow). (C-3) The microscopic view shows tumor remaining within the original LN capsule without any sign of ENE. The metastatic LN showed INI metastasis. *, indicates macroscopic well differentiated and hyperkeratosis of tumor lesion (hematoxylin-eosin stain; original magnification). ENE, extranodal extension; Eso, esophagus; IJV, internal jugular vein; INI, intranodal involvement; LN, lymph node; Lt-RN, left recurrent nerve; SCV, subclavian vein; TR, trachea.

Thoracic field

Thoracic field LNs include the upper thoracic paraesophageal LNs (No. 105), thoracic paratracheal LN (No. 106), recurrent nerve LNs in the mediastinum (No. 106rec), subcarinal LN (No. 107), middle thoracic paraesophageal LNs (No. 108), main bronchus LNs (No. 109), lower thoracic paraesophageal LNs (No. 110), supradiaphragmatic LNs (No. 111), and posteriormediastinal anterior thoracic paraaortic LNs (No. 112) (21,23).

Middle and lower thoracic paraesophageal LN metastases with ENE may invade the adjacent plane including the thoracic duct. These cases show metastatic No. 112 LN with ENE invading the adjacent plane (Figure 9). En bloc resection of the thoracic duct with the surrounding connective layer depends on the presence of ENE invasion. Preoperative imaging diagnosis should assess the ENE grading and invasion (Figure 9).

Figure 9 A 63-year-old man with metastatic No. 112 LN. (A) Contrast-enhanced computed tomography scans. (A-1) Axial view with the enhanced trachea, (A-2) 3D contrast view. Both views showed that the irregular border of No. 112 metastatic LN with ENE (yellow arrow) was adhering to the adjacent plane including the thoracic duct. (B) Surgical view. No. 112 metastatic LN with ENE (yellow arrow) was suspected of invasion to the adjacent plane including the thoracic duct. Blue arrow area shows the area resected with the adjacent plane. (C) Pathological view. The metastatic LN in which carcinoma extended beyond the original nodal area was accompanied by complete destruction of nodal architecture. ENE grade 3. Thoracic duct was suspected of invasion and completely compressed (hematoxylin-eosin stain). Ao, thoracic descending aorta; Azy, azygos vein; Eso, esophagus; LN, lymph node; ENE, extranodal extension; TD, thoracic duct; Ver, vertebra.

The case of ENE and thoracic LN is shown in Figure 10. This case showed minor invasion of ENE; the 3D-CT showed no finding of the presence of ENE. The No. 106rec R LN dissection could be performed with preserving the right recurrent nerve. The pathological result was ENE grade 1. If No. 106rec LN metastases with ENE were suspected in invasion to the recurrent nerve, the recurrent nerve was en bloc resected with the metastatic No. 106rec LN and reconstructed by anastomosis vagus nerve and cervical nerve plexus. The No. 106 LN is located along the anterior and lateral wall of the thoracic trachea; the No. 106rec LNs are located along the recurrent laryngeal nerves in the mediastinum. The superior boundary is drawn from the cephalic border of the subclavian arteries to the suprasternal notch, and the inferior boundary is the caudal border of the recurrent laryngeal nerve curving upward on both sides. The No. 106recR right recurrent nerve LNs are located along the right recurrent laryngeal nerve (21). Other important areas, such as aorta, main broncos, lung, pulmonary artery and vein, might be subject to invasion, not by thoracic metastatic LNs but by the bulky primary tumor of thoracic esophageal cancer.

Figure 10 A 63-year-old man with metastatic No. 106recR LN. (A-1) Axial view with the enhanced trachea, (A-2) 3D contrast view. No. 106recR metastatic LN with ENE invaded the adjacent plane including the Rt-RN and trachea (yellow arrow). (B-1) Surgical view. Metastatic 106recR LN (yellow arrow) was dissected from the Rt-RN and trachea. (B-2) Surgically resected specimen. (C) Pathological view. The metastatic LN in which the carcinoma extended beyond the original nodal area accompanied by complete destruction of the nodal architecture (shown in the red schematic). ENE grade 2 (hematoxylin-eosin stain; original magnification). Eso, esophagus; ENE, extranodal extension; LN, lymph node; IJV, internal jugular vein; Rt-RN, right recurrent nerve; SCV, subclavian vein; SCA, subclavian artery; TR, trachea.

Abdominal field

Abdominal field LNs associated with thoracic esophageal carcinoma include the paracardial LNs (No. 1,2) and LNs along the branch and trunk of the left gastric artery (No. 3,7). The No.7 LNs are located along the trunk of left gastric artery between its root and the origin of its ascending branch (24).

The ENE cases of abdominal LNs are shown in Figure 11. No.7 LN metastases with ENE may invade the left gastric artery. If metastatic LN with ENE has invaded the fundus of stomach, the appropriate gastric tube construction would be required for margin free resection because of the invasion area. The amount of adipose tissue surrounding LNs is more abundant in the abdominal field compared with the cervical and thoracic fields, suggesting that the quantity of adipose tissue may influence the ENE invasion to other adjacent organs between the abdominal and other fields, in contrast to the cervical and thoracic fields.

Figure 11 A 73-year-old man with metastatic No. 7 LN. The irregular border of No. 7 LN with ENE was adhered to the adjacent plane (yellow arrow). (A-1) CT axial view. (A-2) 3D contrast view. No. 7 LN was suspected of ENE invasion to the adjacent plane (yellow arrow). (B) Surgical view. No. 7 LN was en bloc resected with surrounding adipose tissue. (C) Pathological view. The metastatic LN in which carcinoma extended beyond the original nodal area was accompanied by partial destruction of nodal architecture (red color schema). ENE grade 2. There was invasion to LGA (red arrow) (hematoxylin-eosin stain; original magnification). AA, abdominal aorta; IVC, inferior vena cava; LGA, left gastric artery; LN, lymph node; Panc, pancreas; Sto, stomach.

Strengths and limitations

This study is the first report to assess the correlation between 3D-CT findings and pathological ENE in esophageal cancer. This atlas additionally analyzes the correlation between 3D-CT imaging findings and pathological findings with the information of surgical findings.

We previously reported that a positive circumferential resection margin is a prognostic factor for survival (25). The incision end-line is easily determined in abdominal organs, unlike for the esophagus in the thoracic cavity, because of the abundant connective tissue in the abdominal cavity. Therefore, circumferential resection margin status can be a critical predictor for the prognosis of ESCC patients, which may be applicable to the dissected margin status of ENE.

The following were limitations to this study: (I) our small sample size may increase the risk of type I error. Further validation is necessary, preferably through larger studies or external data sets; (II) MRI could not accurately show mediastinal LNs because of the influence of the cardiopulmonary pulse; (III) some ESCC patients were included who had undergone neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy; (IV) the pathological invasion area cannot be correctly evaluated by only 3D-CT. ENE Grade 1 could not be accurately diagnosed because of the macroscopic minor invasion of ENE. Additional biomarker imaging, such as dual energy CT, is required for correct evaluation of the ENE, and (V) EUS and fine needle aspiration cytology (EUS-FNAC) are indeed important complementary modalities for assessing nodal involvement and tumor characteristics in esophageal carcinoma. EUS provides high-resolution images, allowing for detailed evaluation of the layers of the esophageal wall and adjacent structures. FNAC, when combined with EUS, can enhance diagnostic accuracy by enabling direct sampling of suspicious LNs. In our study, we focused on CT imaging as it is more widely available and non-invasive, making it suitable for routine clinical practice. We acknowledge that combining CT findings with EUS or EUS-FNAC could potentially improve diagnostic accuracy, and this integration warrants further investigation in future studies.

Conclusions

Here we present an atlas of correlations between 3D-CT imaging findings and pathological findings with the information of surgical findings, which might be useful for accurate diagnosis. Accurate clinical diagnosis of ENE is important to plan the appropriate multimodality treatment and to predict not only prognosis but also the difficulty of the surgical procedure during LN dissection. Knowledge of the pattern of the ENE LN on each field and findings of invasions of the crucial structure will help determine treatment strategy (Figure S1). Based on these findings, a randomized accuracy test by radiologists may be needed.

Acknowledgments

The authors would like to thank Mototaka Miyake for his contribution to this article in terms of the concept of this study. The authors also thank Masami Mukai for her contribution to this article in terms of data collection. The authors also especially thank NOIE corporation for the lymph node schema. We thank Gabrielle White Wolf, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

Footnote

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-34/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-34/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All clinical procedures described in this study was conducted in accordance with the Helsinki Declaration (as revised in 2013). This study was performed with ethical approval from the Medical Ethics Committee of the Teine Keijinkai Hospital (No. 2-021299-00) and informed consent was obtained from all individual participants for publication of this article and accompany images.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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